Synthetic Toll-Like Receptor 4 Agonist Enhances Vaccine Efficacy in an Experimental Model of Toxic Shock Syndrome

Abstract

The development of new protein subunit vaccines has stimulated the search for improved adjuvants to replace traditional aluminum-containing products. We investigated the adjuvant effects of a synthetic Toll-like receptor 4 (TLR4) agonist on vaccine efficacy in an experimental model of toxic shock syndrome. The TLR4 agonist E6020 has a simplified structure consisting of a hexa-acylated acyclic backbone. The vaccine examined is a recombinantly attenuated form of staphylococcal enterotoxin B (STEBVax). Using cells stably transfected with TLRs, E6020 transduced signals only through TLR4, suggesting monospecificity, while Escherichia coli 055:B5 lipopolysaccharide activated both the TLR2/6 heterodimer and TLR4. Coadministration of E6020 with STEBVax, by the intramuscular or intranasal route, induced significant levels of immunoglobulin G (IgG) in BALB/c mice. Further, increased IgG production resulted from the combination of E6020 with aluminum hydroxide adjuvant (AH). The antibody response to the vaccine coadministered with E6020 was a mixed Th1/Th2 response, as opposed to the Th2-biased response obtained with AH. Mice vaccinated with STEBVax coadministered with AH, TLR4 agonists, or a combination of both adjuvants were protected from toxic shock. Our data demonstrate the effectiveness of the synthetic TLR4 agonist E6020 as an alternative adjuvant for protein subunit vaccines that may also be used in combination with traditional aluminumcontaining adjuvants.

Nasal Immunity to Staphylococcal Toxic Shock Is Controlled by the Nasopharynx-Associated Lymphoid Tissue

“…Efficacy significantly increased if the vaccine was coadministered IN with a TLR4 agonist (30), suggesting that priming of nasopharyngeal immune components may contribute to immunity.…”

“…The follicule-associated epithelial cells (FAE) of the NALT are intercalated by M cells, responsible for antigen retrieval from the mucosal surfaces of the air passages and transport across the epithelial layer to dendritic cells below (33). An important feature of M cells present in the NALT is the abundance of TLR4 in their luminal location (43), which may explain the increased efficacy of the rSEBv vaccine when combined with TLR4 agonists (30). In addition to its functions as an antigen-surveillance and processing organ, the NALT may further contribute to overall immunity as a source of IgA-secreting plasma cells (50,51).…”

“…We previously designed a recombinant SEB vaccine (rSEBv) that protects against lethal TSS in mice and rhesus macaques (44). Intranasal (IN) vaccination with rSEBv provides protection against wild-type (wt) SEB challenge in mice (30). The rSEBv was tested in combination with various adjuvants, including alum-based adjuvants and Toll-like receptor (TLR) agonists.…”

TLR4 Ligands Augment Antigen-Specific CD8 + T Lymphocyte Responses Elicited by a Viral Vaccine Vector

“…TLR ligands have therefore emerged as potential vaccine adjuvants, particularly in the context of peptide, protein, and DNA vaccines (17). In particular, TLR agonists are widely reported to modulate antibody and T helper lymphocyte responses, and in some cases CD8 ϩ T lymphocyte responses, elicited by protein-based vaccines (5,19,33,41). However, far less is known about the impact of TLR ligands on the immunogenicity of viral vector-based vaccines.…”

Examining the Role of Nasopharyngeal-associated Lymphoreticular Tissue (NALT) in Mouse Responses to Vaccines

“…Mice were administered STEBVax by intranasal (IN) or intraperitoneal (IP) routes. The vaccine was formulated with an adjuvant that activates the Toll-like receptor 4 pathway 3,14 , and controls were given only saline or vaccine without adjuvant. Cultured NALT obtained from experimental groups secreted antigen-specific immunoglobulins into medium that was measurable by ELISA.…”